5-HT1A Receptor Research Articles

Brexpiprazole augmentation in treatment-resistant obsessive-compulsive disorder: a preliminary retrospective observational study

Obsessive-compulsive disorder (OCD) is a chronic illness associated with significant functional impairment. Monotherapy with serotonin reuptake inhibitors (SRIs) often leads to only partial improvement of symptoms. In such cases, a common, well established, treatment approach for most patients is the augmentation of SRI therapy with antipsychotic medications. Brexpiprazole is an atypical antipsychotic agent that acts as a partial agonist of 5-HT1A, D2, and D3 receptors. Purpose of this retrospective observational study was to evaluate the effectiveness and tolerability of brexpiprazole as augmentation to SRIs in patients with treatment-resistant OCD. This preliminary study included a sample of 10 patients diagnosed with treatment-resistant OCD who underwent a 12-week trial of augmentative brexpiprazole, starting at a dose of 1 mg/day, with dosage adjustments based on clinical judgment. Treatment response was assessed through changes in the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) total score from baseline to the end of the 12-week observation period. Adverse events were systematically recorded. Significant improvement was observed after the 12-week period: at the endpoint, seven patients (70%) achieved a ≥25% reduction in Y-BOCS total score compared to baseline, with five of them (50% of the overall sample) showing a more robust clinical response (≥35% reduction). Mild adverse effects, such as sedation and weight gain, were reported by two participants (20% of the overall sample). These findings suggest that brexpiprazole may offer a promising effectiveness and tolerability profile in the management of treatment-resistant OCD.

Discovery of a Novel Multitarget Analgesic Through an In Vivo-Guided Approach

Background: Pain is a complex condition influenced by peripheral, central, immune, and psychological factors. Multitarget approaches offer a more effective and safer alternative to single-target analgesics by enhancing efficacy, reducing side effects, and minimizing tolerance. This study aimed to identify a novel multitarget analgesic with improved pharmacological properties. Methods: An in vivo-guided screening approach was used to discover a new analgesic compound. Compound 29, derived from a novel scaffold inspired by opiranserin and vilazodone pharmacophores, was identified through analog screening in the formalin test. Its efficacy was further evaluated in the spinal nerve ligation (SNL) model of neuropathic pain. Mechanistic studies explored its interaction with neurotransmitter transporters and receptors, while pharmacokinetic and safety assessments were conducted to determine its stability, brain penetration, and potential toxicity. Results: Compound 29 demonstrated high potency in the formalin test, with an ED50 of 0.78 mg/kg in the second phase and a concentration-dependent effect in the first phase. In the SNL model, it produced dose-dependent analgesic effects, increasing withdrawal thresholds by 24% and 45% maximum possible effect (MPE) at 50 and 100 mg/kg, respectively. Mechanistic studies revealed strong triple uptake inhibition, particularly at dopamine (DAT) and serotonin (SERT) transporters, alongside high-affinity 5-HT2A receptor antagonism. Pharmacokinetic analysis indicated enhanced stability and blood–brain barrier permeability. In vitro studies confirmed its nontoxicity to HT-22 cells but revealed potential hERG inhibition and strong CYP3A4 inhibition. Conclusions: Compound 29 is a promising multitarget analgesic with potent efficacy and favorable pharmacokinetics. Ongoing optimization efforts aim to mitigate side effects and enhance its therapeutic profile for clinical application.

The Secure Therapeutic Effects of Recently Developed Antipsychotic Drugs and Updated Neural Networks in Schizophrenia

Introduction: Schizophrenia and schizoaffective disorder are treated in most cases with antipsychotic drugs of the second generation. These drugs block dopaminergic and serotonergic receptors, i.e., D2 and 5-HT2A receptors, and cause different adverse effects, for example, movement disturbances of the extrapyramidal system and adverse effects of vital parameters and of the heart. These drugs treat positive symptoms in schizophrenia and, to a lesser extent, negative symptoms. This review presents the development of newer antipsychotic drugs. Methods/Material: References were taken from PubMed after using the following keywords: schizophrenia, schizoaffective disorder, antipsychotic drug, neurotransmitter and neuropeptide. Among these newer antipsychotic drugs are cariprazine, brexipiprazole and lumateperone, which exert a partial agonistic effect at D2 and 5-HT2A receptors, pimavanserin, a 5-HT2A receptor antagonist which treats negative symptoms in schizophrenia as an add-on therapy, olanzapine combined with samidorphan, which reduces weight gain, and M4 or M1 receptor agonists, for example, xanomeline with an antipsychotic effect combined with trospium, an anticholinergic drug. Neural networks were updated in order to deduce the antipsychotic mechanism of action of newer antipsychotic drugs, especially xanomeline. Results: The newer antipsychotic drugs cariprazine, brexipiprazole and lumateperone show antipsychotic, antimanic and anti-depressive effects, however, the efficacy on psychotic symptoms in long-term treatment has not yet been examined. Pimavanserin reduces negative symptoms in schizophrenia as an additional pharmacotherapy to treat this disorder. Olanzapine combined with samidorphan exerts good antipsychotic effects and reduces weight gain. The new antipsychotic drug xanomeline, the antipsychotic effect of which is quite different from the antidopaminergic effect, treats positive and negative symptoms in schizophrenia. Its mechanism of action was deduced from the neural networks presented. The long-term efficacy should still be examined. Conclusion: This review is focused on newer antipsychotic drugs. The long-term efficacy of cariprazine, brexipiprazole and lumateperone in the treatment of schizophrenia should be examined furthermore. Neural networks in the brain areas involved in schizophrenia should be examined and updated furthermore. Newer antipsychotic drugs, for example, xanomeline, an M4 or M1 receptor agonist, which has been combined with trospium, an anticholinergic drug, the mechanism of action of which can be derived from the neural network suggested in this review.

Effect of antidepressants and social defeat stress on the activity of dorsal raphe serotonin neurons in free-moving animals.

Major depressive disorder (MDD) is among the most common mental disorders worldwide and is characterized by dysregulated reward processing associated with anhedonia. Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for MDD; however, their onset of action is delayed. Recent reports have shown that serotonin neurons in the dorsal raphe nucleus (DRN) are activated by rewards and play a vital role in reward processing. However, whether antidepressant treatment affects the DRN serotonin neuronal response to rewards in awake animals remains unknown. In this study, we measured the activity of DRN serotonin neurons in awake mice and determined the effects of antidepressants and chronic stress on DRN serotonin neuronal activity. We found that acute treatment with citalopram, an SSRI, significantly decreased sucrose-induced activation of DRN serotonin neurons. The decrease in response to acute citalopram treatment was attenuated by chronic citalopram treatment. Acute treatment with (S)-WAY100135, a 5-HT1A receptor antagonist, dose-dependently inhibited the response to acute citalopram treatment. These results indicate that autoinhibition by activating 5-HT1A receptors via acute SSRI treatment may blunt the reward response, which can be recovered after chronic SSRI treatment.

Potential Serotonin 5-HT2A Receptor Agonist of Psychoactive Components of Silene undulata Aiton: LC-MS/MS, ADMET, and Molecular Docking Studies.

Silene undulata is historically used for inducing vivid and prophetic lucid dreams, but limited information exists on its phytochemical composition and potential pharmacological properties. This study aimed to investigate the phytochemical composition of S. undulata through LC-MS/MS analysis and explore its potential serotonergic activity, which could support and confirm the traditional use of S. undulata as a dream-inducing plant. LC-MS/MS analysis was conducted on S. undulata extract, identifying 51 phytochemicals, including norharman, harmalol, harmaline, harmine, and ibogaine alkaloids. ADMET and Molecular docking investigations were employed to assess the serotonergic potential of these compounds. The analysis revealed the presence of β-carboline alkaloids, such as norharman, harmalol, harmaline, harmine, and ibogaine, within S. undulata extract. ADMET analysis showed that these compounds have a favourable pharmacokinetic properties. In addition, molecular docking investigations showed that harmaline (-8.90 Kcal/mol), harmalol (-8.56 Kcal/mol), and ibogaine (-8.75 Kcal/mol) exhibited binding affinities comparable to the control molecule, LSD (-9.14 Kcal/mol), indicating potential agonistic activity at serotonin 5-HT2A receptor. These findings provide insights into the potential therapeutic benefits of S. undulata, supporting its traditional use as a psychoactive plant. This study investigated the chemical constituents and potential serotonergic agonist activity of S. undulata for the first time. While promising, further research is necessary to uncover additional medicinal properties associated with the identified phytochemical components.

Low (micro)doses of 2,5-dimethoxy-4-propylamphetamine (DOPR) increase effortful motivation in low-performing mice.

Treating amotivated states remains difficult. Classical psychedelic drugs (5-HT2A receptor agonists) such as LSD and psilocybin have shown therapeutic potential in treating such symptoms, but their development has been hindered by their undesirable hallucinogenic effects. There is increasing evidence that administration of psychedelics at dose levels too low to evoke a hallucinogenic effect ("microdoses") may have therapeutic value in contexts of mood and cognition. 2,5-Dimethoxy-4-propylamphetamine (DOPR) is a psychedelic phenethylamine compound acting as a 5-HT2A receptor agonist. We used a combination of behavioral assays to determine the motivational and hallucinogenic-like effects of DOPR and identify the dose ranges at which each of these effects were observed. In mice, the motivational effects of psychedelic compounds were assessed using the progressive ratio breakpoint task (PRBT, n=80), a translational assay sensitive to changes in motivation. Psychedelic-like effects were gauged using the mouse head-twitch response (HTR, n=72) assay, a preclinical readout of psychedelic potential. Significant improvements in PRBT performance were seen at doses as low as 0.0106 mg/kg in animals with low baseline PRBT scores while high-performing PRBT mice were unaffected. DOPR only induced significant HTR at doses ≥0.1 mg/kg. Together, these results indicate that the psychedelic DOPR may increase motivation in those with a low motivated state. Importantly, these effects may be attainable at low doses below the threshold required to induce psychedelic subjective effects. Hence, the ability of low doses of DOPR and other psychedelic drugs to alleviate amotivated states in rodents manipulated to induce disease-relevant states should be investigated.

Psychedelics in neuroinflammation: Mechanisms and therapeutic potential.

Neuroinflammation is a critical factor in the pathogenesis of various neurodegenerative and psychiatric disorders, including Alzheimer's disease, Parkinson's disease, and major depressive disorder. Psychedelics, such as psilocybin, lysergic acid diethylamide (LSD), and dimethyltryptamine (DMT), have demonstrated promising therapeutic effects on neuroinflammation, primarily through interactions with serotonin (5-HT) receptors, particularly the 5-HT2A receptor. Activation of these receptors by psychedelics modulates the production of pro-inflammatory cytokines, regulates microglial activity, and shifts the balance between neurotoxic and neuroprotective metabolites. Additionally, psychedelics affect critical signaling pathways, including the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), and mechanistic target of rapamycin (mTOR) pathways, promoting neuroplasticity and exerting anti-inflammatory effects. Beyond the serotonergic system, other neurotransmitter systems-including the glutamatergic, dopaminergic, noradrenergic, gamma-aminobutyric acid (GABAergic), and cholinergic systems-also play significant roles in mediating the effects of psychedelics. This review examines the intricate mechanisms by which psychedelics modulate neuroinflammation and underscores their potential as innovative therapeutic agents for treating neuroinflammatory and neuropsychiatric disorders.

Exploring the Ameliorative Effects of Omega-3 Fatty Acid Supplementation on Maternal Behavioral Abnormalities Induced by Prenatal Chronic Restraint Stress.

Maternal behavior is a complex form of social conduct exhibited, which directly influences the brain development and emotional behavior of offspring. Studies have shown that stress significantly impacts maternal behavior, with the 5-HT (serotonin) system playing a crucial role in this process OBJECTIVE: This study aims to explore the ameliorative effects of omega-3 fatty acid supplementation on maternal behavioral abnormalities induced by prenatal chronic restraint stress, and to analyze the molecular mechanisms involved METHODS: Sprague-Dawley rats were divided into control, stress, and stress+omega-3 (500mg/kg) groups. Depressive behaviors were assessed using the sucrose preference test and forced swimming test. The regulatory effects of Omega-3 on maternal behavior following stress were analyzed by measuring 5-HT levels, 5-HT receptors, 5-HT1A receptor expression, downstream cAMP levels, inflammatory markers (IL-1β, TNF-α, and IL-6), and oxidative stress responses (MDA levels) RESULTS: The stress group exhibited significant reductions in maternal behaviors, such as delayed pup retrieval and decreased licking time. Omega-3 supplementation effectively improved these abnormalities, enhancing maternal care and reducing violent behaviors. Mechanistically, omega-3 supplementation increased 5-HT and receptor expression, reduced inflammation and oxidative stress, and promoted neuronal function recovery CONCLUSION: Omega-3 fatty acids can effectively mitigate the negative impact of chronic stress on maternal behavior. The underlying mechanisms involve the regulation of the 5-HT system and the reduction of neuroinflammation. This finding provides a theoretical basis for clinical interventions targeting stress-related maternal behavior disorders.

Jiawei Suanzaoren decoction for the treatment of perimenopausal insomnia: clinical observation and experimental study

BackgroundTraditional Chinese medicine has a good clinical therapeutic effect on perimenopausal insomnia, Jiawei Suanzaoren Tang (JW-SZRT) has a significant therapeutic effect on people with yin deficiency and fire excess type insomnia.MethodFirstly, 80 cases of perimenopausal yin deficiency and fire excess type insomnia were included in the study. The treatment group was treated with Jiawei Suanzaoren decoction, while the control group was treated with lorazepam for 4 weeks. The study observed and compared the Pittsburgh Sleep Quality Index (PSQI), Kupperman score, Polysomnography (PSG) and sex hormone levels of two groups before and after treatment. Secondly, we also conducted network pharmacology analysis and mechanism research. We first searched public databases for the targets of the compound known tobe associated with JW-SZRT, as well as those predicted to be targets of insomnia, and then used software Cytoscape 3.7.2, GO and KEGG to identify enriched gene pathways and networks. Networks and pathways that overlapped between Insomnia-associated proteins and JW-SZRT target proteins were then used to predict candidate protein targets of JW-SZRT in insomnia. Finally, 40 rats were selected in animal experimentation and 30 perimenopausal insomnia rat models were created through ovariectomy and a modified multi-platform water environment 72-hour sleep deprivation method. The model group received normal saline, the western medicine group received lorazepam suspension, and the Chinese medicine group received Jiawei Suanzaoren decoction. The sham surgery group was given routine feeding. The sleep condition, the levels of blood hormone levels and the expression levels of 5-Hydroxytryptamine (5-HT) and Gamma-Aminobutyric Acid receptor A (GABAA) receptor in the hypothalamus were compared between groups.ResultsIn clinical observation, the sleep condition and the changes of hormone levels between the treatment group and the control group were statistically significant (P < 0.05). The results of network pharmacology indicate that in the main signaling pathways for treating insomnia, it is speculated that Jiawei Suanzaoren Tang can regulate the signaling pathway of neuroactive ligand receptor interactions by inhibiting the activation of related proteins, thereby improving sleep. Animal experiments have also shown that the JW-SZRT can significantly improve the sleep conditions of insomnia rats during perimenopause, and the expression levels of 5-HT and GABAA receptors in the hypothalamus had a significant difference between groups in animal experiments (P < 0.05).ConclusionJiawei Suanzaoren Decoction can improve the perimenopausal insomnia. The mechanism behind this improvement may be related to the regulation of Estradiol (E2), Follicle-Stimulating Hormone (FSH), and luteinizing hormone (LH) levels, as well as the mRNA expression levels of 5-HT1a, 5-HT2a, GABAARα1, and GABAARγ2 receptors in the hypothalamus.

Molecular insights into the modulation of the 5HT2A receptor by serotonin, psilocin, and the G protein subunit Gqα.

5HT2AR is a G-protein-coupled receptor that drives many neuronal functions and is a target for psychedelic drugs. Understanding ligand interactions and conformational transitions is essential for developing effective pharmaceuticals, but mechanistic details of 5HT2AR activation remain poorly understood. We utilized all-atom molecular dynamics simulations and free-energy calculations to investigate 5HT2AR's conformational dynamics upon binding to serotonin and psilocin. We show that the active state of 5HT2AR collapses to a closed state in the absence of Gqα, underscoring the importance of G-protein coupling. We discover an intermediate "partially-open" receptor conformation. Both ligands have higher binding affinities for the orthosteric than the extended binding pocket. These findings enhance our understanding of 5HT2AR's activation and may aid in developing novel therapeutics. Impact statement This study sheds light on 5HT2AR activation, revealing intermediate conformations and ligand dynamics. These insights could enhance drug development for neurological and psychiatric disorders, benefiting researchers and clinicians in pharmacology and neuroscience.

Exploring Serotonin-1A receptor function in the effects of buspirone on cognition by molecular receptor expression and EEG analytical studies.

Buspirone, a commonly prescribed medication for generalized anxiety disorder (GAD), is gaining attention for its narrow window of side effects such as lack of physical dependence, non-sedative properties as compared to other anxiolytic drugs. Its dose-specific therapeutic effects beyond anxiety highlights its clinical significance. Pharmacologically, buspirone activates serotonin-1A pre-synaptic autoreceptors and post-synaptic heteroreceptors which modulate serotonergic neurotransmission induced behavioral changes such as anxiolytic and nootropic effects. This study explored change in neural activity associated serotonin-1A receptors, induced by repeated administration of buspirone at specific doses (0.1 mg/kg and 3 mg/kg). Buspirone induced behavioral changes were assessed by Morris Water Maze (MWM) for cognitive functions, Elevated Plus Maze (EPM) for anxiety, RT-PCR (Reverse transcriptase-polymerase chain reaction) for 5-HT1A receptor expression levels, and EEG (electroencephalography) analysis of neuronal electrical activity in the frontal cortex. Our findings revealed that a low dose of buspirone (0.1 mg/kg) significantly enhanced spatial learning and memory compared to high dose (3 mg/kg). Low-dose treatment elevated mRNA expression levels of serotonin-1A receptors in hippocampus and decreased in midbrain raphe nuclei, with the opposite patterns observed in the high dose. In addition, EEG spectral analysis have revealed dose specific cross coupling frequency of theta-gamma and delta-beta brain waves. At low dose (0.1mg/kg) positive correlation of theta-gamma coupling effect and negative correlation of delta beta as decoupling effect were observed. Conversely, at high dose (3mg/kg), results showed opposite pattern with weak correlation of theta gamma coupling effect and positive correlation of delta-beta as coupling effect. These results suggest that buspirone enhances learning and memory with differential activation of pre and postsynaptic serotonin-1A receptors, altering its expression levels which influence neural activity associated with theta-gamma and delta-beta coupling effects. It provides valuable molecular insights on clinical significance of buspirone in mitigating neuropathological disorders such as behavioral disorders and neurocognitive decline associated with disrupted regulation of serotonin-1A neurotransmission at specific doses. Our findings provide molecular insights of dose dependent therapeutic potential of buspirone against neuropathological symptoms of behavioral disorders, neurocognitive decline associated with dysregulated serotonin-1A neurotransmission.

Exploring DMT: Endogenous Role and Therapeutic Potential.

N,N-Dimethyltryptamine (DMT) is a naturally occurring amine and psychedelic compound, found in plants, animals, and humans. While initial studies reported only trace amounts of DMT in mammalian brains, recent findings have identified alternative methylation pathways and DMT levels comparable to classical neurotransmitters in rodent brains, calling for a re-evaluation of its biological role and exploration of this inconsistency. This study evaluated DMT's biosynthetic pathways, focusing on indolethylamine N-methyltransferase (INMT) and its isoforms, and possible regulatory mechanisms, including alternative routes of synthesis and how physiological conditions, such as stress and hypoxia influence DMT levels. This review considers the impact of endogenous regulatory factors on DMT synthesis and degradation, particularly under conditions affecting monoamine oxidase (MAO) efficiency and activity. We also examined DMT's potential roles in various physiological processes, including neuroplasticity and neurogenesis, mitochondrial homeostasis, immunomodulation, and protection against hypoxia and oxidative stress. DMT's lipophilic properties allow it to cross cell membranes and activate intracellular 5-HT2A receptors, contributing to its role in neuroplasticity. This suggests DMT may act as an endogenous ligand for intracellular receptors, highlighting its broader biological significance beyond traditional receptor pathways. The widespread evolutionary presence of DMT's biosynthetic pathways across diverse species suggests it may play essential roles in various developmental stages and cellular adaptation to environmental challenges, highlighting the neurobiological significance of DMT and its potential clinical applications. We propose further research to explore the role of endogenous DMT, particularly as a potential neurotransmitter.

The temporal copulatory patterns of female rat sexual behavior.

Female sexual behavior is a naturally rewarding activity that plays an important role in reproduction and species survival. For female rats, regulating the timing of sexual interactions is essential for optimizing mating satisfaction and enhancing the physiological conditions needed for successful fertilization. So far, traditional research on female sexual behavior has relied on a limited set of behavioral parameters, which has certain shortcomings. To address this, our study aimed to develop a more detailed behavioral framework for assessing temporal copulatory patterns in female rats. We compared fully receptive females and less-receptive females, while also investigating the effects of (R)-(+)-8-OH-DPAT, a 5-HT1A receptor agonist known for its inhibitory impact on female sexual behavior. Additionally, we examined how sexual experience and pacing conditions influence these copulatory patterns. Our results revealed that female rats engage in structured patterns of sexual bouts and time-outs, with higher receptivity leading to more sexual bouts and shorter time-outs. This suggests that sexual bouts can be viewed as an indicator of copulatory speed, while time-outs reflect motivation to continue mating. Sexual experience did not enhance sexual performance but did result in females receiving more copulatory events from males. Lastly, we found that the conditions under which mating occurs (paced vs. non-paced) may not significantly impact copulatory behavior in fully-receptive females, but could be more relevant for less-receptive females. Despite this, paced mating conditions remain preferable for studying female sexual behavior.

An Unexpected Activity of a Minor Cannabinoid: Cannabicyclol (CBL) Is a Potent Positive Allosteric Modulator of Serotonin 5-HT1A Receptor.

Cannabicyclol ((±)-CBL), a minor phytocannabinoid, is largely unexplored, with its biological activity previously undocumented. We studied its conversion from cannabichromene (CBC) using various acidic catalysts. Montmorillonite (K30) in chloroform at room temperature had the highest yield (60%) with minimal byproducts. Key reaction conditions, such as solvent, temperature, and time, significantly impacted the yield. The structure of (±)-CBL was confirmed via X-ray crystallography. Stability studies showed that (±)-CBL and its MCT oil dilution remain stable at 25-40 °C for three months. Radioligand binding assays revealed high affinity of CBL for the 5-HT1A receptor but weak interaction with CB1 and CB2 receptors. At 10 μM and 1 μM, (±)-CBL inhibited [3H]-8-hydroxy-DPAT binding to 5-HT1A by 75% and 20%, respectively. Functional assays showed that (±)-CBL acts as a weak agonist at high concentrations but a potent positive allosteric modulator of serotonin-induced activation at low concentrations. At 4 μM, (±)-CBL increased serotonin-induced β-arrestin recruitment from 20% to 80%. This unique modulatory profile highlights the potential of (±)-CBL in drug discovery targeting serotonin receptors.

Enhancement of neurogenesis and antidepressant-like efficacy through combined activation of Sigma-1 and 5-HT1A receptors: focus on Sigma-1-5-HT1A heteroreceptor complex.

The sigma-1 receptor (S1R) attracts significant interests as a potential target for rapid-onset antidepressant-like effects, particularly due to its capacity to swiftly stimulate serotonergic neurons in the dorsal raphe nucleus (DRN). However, the precise regulatory mechanism involved remains unclear. Therefore, this study aims to examine the interaction between the selective S1R agonist, SA-4503 and 8-OH-DPAT, a serotonin1A (5-HT1A) receptor agonist, in mice with depressive-like behavior induced by chronic restraint stress (CRS). Preliminary investigations were conducted to explore the potential mechanisms underlying the accelerated antidepressant-like effect regulated by the combined activation of S1R and 5-HT1A receptors. The results showed that the coadministration of SA4503 (1.0 mg/kg, i.g.), a selective S1R agonist, and 8-OH-DPAT (0.3 mg/kg, i.g.) produces antidepressant-like effects. However, the doses of 8-OH-DPAT employed in this study lack intrinsic antidepressant-like activity in this model. Moreover, using an in-situ proximity ligation assay obtained the first evidence of S1R-5-HT1A heteroreceptor complexes in the midbrain DRN and dentate gyrus (DG) of the forebrain in mice. The formation of these heterocomplexes is influenced by pharmacological agents and is also closely associated with the development of depressive-like behaviors in mice. Mechanistically, combined treatment with S1R and 5-HT1A agonists showed a synergistic effect on neurogenesis and plasticity in the dorsal DG region of the hippocampus in CRS mice. Our findings significantly advanced our understanding of S1R-mediated neuroplasticity, suggesting new therapeutic strategies for developing rapid-acting antidepressants.

N, N-dimethyltryptamine (DMT) in rodent brain: Concentrations, distribution, and recent pharmacological data.

Renewed interest in the clinical use of psychedelic drugs acknowledges their therapeutic effectiveness. It has also provided a changing frame of reference for older psychedelic drug study data, especially regarding concentrations of N, N-dimethyltryptamine (DMT) reported in rodent brains and recent discoveries in DMT receptor interactions in rat brain neurons and select brain areas. The mode of action of DMT in its newly defined role as a neuroplastogen, its effectiveness in treating neuropsychiatric disorders, and its binding to intracellular sigma-1 and 5HT2a receptors may define these possible roles. Recent data also show psychedelics promote neuroplasticity via activation of sigma-1 receptors associated with the endoplasmic reticulum and binding to 5-HT2a receptors predominantly related to the intracellular membrane of the Golgi apparatus in cortical neurons and the failure of DMT to occupy cell surface 5-HT2a receptors. While DMT has been proposed as the endogenous ligand for sigma-1, there is no identified ligand for intracellular 5-HT2a receptors, which serotonin cannot acquire. DMT is proposed to be the missing endogenous ligand. These data further suggest that DMT may be involved in brain development in rat pups. Brain levels of DMT have also been shown to be elevated by stress in the rat and appear to be under an inducible, adaptive, physiological regulatory system control. With DMT acting as the natural ligand for intracellular 5HT2a receptors in the Golgi, it may also explain the subjective effects observed from the administration of psychedelics in general and define some of the natural roles for DMT in particular.

CBD and the 5-HT1A receptor: A medicinal and pharmacological review.

Cannabidiol (CBD), a phytocannabinoid, has emerged as a promising candidate for addressing a wide array of symptoms. It has the ability to bind multiple proteins and receptors, including 5-HT1AR, transient receptor potential vanilloid 1 (TRPV1), and cannabinoid receptors. However, CBD's pharmacodynamic interaction with 5-HT1AR and its medicinal outcomes are still debated. This review explores recent literature to elucidate these questions, highlighting the neurotherapeutic outcomes of this pharmacodynamic interaction and proposing a signaling pathway underlying the mechanism by which CBD desensitizes 5-HT1AR signaling. A comprehensive survey of the literature underscores CBD's multifaceted neurotherapeutic effects, encompassing antidepressant, anxiolytic, neuroprotective, antipsychotic, antiemetic, anti-allodynic, anti-epileptic, anti-degenerative, and addiction-treating properties, attributable in part to its interactions with 5-HT1AR. Furthermore, evidence suggests that the pharmacodynamic interaction between CBD and 5-HT1AR is contingent upon dosage. Moreover, we propose that CBD can induce desensitization of 5-HT1AR via both homologous and heterologous mechanisms. Homologous desensitization involves the recruitment of G protein-coupled receptor kinase 2 (GRK2) and β-arrestin, leading to receptor endocytosis. In contrast, heterologous desensitization is mediated by an elevated intracellular calcium level or activation of protein kinases, such as c-Jun N-terminal kinase (JNK), through the activity of other receptors.

Pharmacological characterization of cannabidiol as a negative allosteric modulator of the 5-HT2A receptor.

Promising clinical evidence suggests that psychedelic compounds, like lysergic acid diethylamide (LSD), have therapeutic value for treatment of psychiatric disorders. However, they often produce hallucinations and dissociative states, likely mediated by the serotonin (5-HT) receptor 5-HT2A, raising challenges regarding therapeutic scalability. Given the reported antipsychotic effects of cannabidiol (CBD) and its promiscuous binding at many receptors, we assessed whether CBD could modulate 5-HT2A signalling. Activation of the 5-HT2A intracellular signalling events were assessed using resonance energy transfer- or fluorescence-based biosensors in HEK 293 cells and in rat primary cortical neurons. In 5-HT2A-transfected HEK 293T cells, CBD antagonized LSD-mediated Gq activation in a saturable way, while leaving β-arrestin2 recruitment unaffected. CBD decreased Gq activation mediated by the 5-HT2A-specific agonist DOI as well as LSD-mediated activity in primary rat neonatal cortical neurons. Using Site Identification by Ligand Competitive Saturation (SILCS) simulations, we also predicted that the putative binding site of CBD overlapped with that of oleamide, a positive allosteric modulator of 5-HT2A, and could displace the binding of orthosteric ligands toward the external binding pocket. Based on these findings, we propose that CBD acts as a negative allosteric modulator of 5-HT2A.

The unique role of fluoxetine in alleviating depression and anxiety by regulating gut microbiota and the expression of vagus nerve-mediated serotonin and melanocortin-4 receptors.

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) widely used for depression, but its potential effects on gut microbiota regulation and vagus nerve-mediated serotonin receptor expression have not been well studied. We investigated changes in the gut microbiome regulated by fluoxetine and vagus nerve-mediated expression of several serotonin (5-HT) receptor types associated with anxiety and depression. Oral administration of fluoxetine alleviated lipopolysaccharide (LPS)-induced depressive and anxiety behaviors, increased 5-HT1A, 2 C, and melanocortin 4 (MC4) receptor expression, and the composition of Lactobacillus in mice's gut microbiome. In contrast, in the vagotomized group, fluoxetine did not modulate behaviors and receptor expression. Increased Lactobacillus composition was found to correlate significantly with behavioral test results. The importance of Lactobacillus growth to the efficacy of fluoxetine was confirmed by the effectiveness of fluoxetine, which was reduced by co-administering antibiotics. To determine the additional impact of the gut microbiome, we isolated Limosilactobacillus reuteri and Ligilactobacillus murinus, which were increased in the fluoxetine-treated group and administrated. The results showed that administration of each strain improved anxious or depressive behavior, as did fluoxetine, and vagotomy eliminated these effects. These results suggest that fluoxetine administration increases the proportion of Lactobacillus in the gut, which modulates 5-HT1A, 2 C, and MC4 receptor expression through the enteric nervous system and improves depression.

Postcolitis Alterations in Dose-Dependent Effects of 5-HT1A Agonist Buspirone on Nociceptive Activity of the Raphe Magnus and Dorsal Raphe Neurons in Rats.

The serotonergic raphe magnus (RMg) and dorsal raphe (DR) nuclei are crucial pain-regulating structures, which nociceptive activity is shown to be altered in gut pathology, but the underlying neuroplastic changes remain unclear. Considering the importance of 5-HT1A receptors in modulating both pain and raphe neuronal activity, in this study, we aimed to determine whether 5-HT1A-dependent visceral and somatic nociceptive processing within the RMg and DR is modified in postcolitis conditions. In anaesthetised male Wistar rats, healthy control and recovered from TNBS-induced colitis, the microelectrode recordings of RMg and DR neuron responses to noxious colorectal distension (CRD) or tail squeezing (TS) were performed prior and after intravenous administration of 5-HT1A agonist, buspirone. In postcolitis animals, 5-HT1A autoreceptor- and heteroreceptor-activating high doses of buspirone (2 and 4 mg/kg) lost normally occurring ability to facilitate CRD- and TS-evoked activation of RMg neurons, causing inhibition of the local nociceptive signalling similar to 5-HT1A autoreceptor-activating low doses (0.1 and 0.5 mg/kg). Conversely, the normally inherent property of buspirone at all doses to reduce visceral and somatic pain-related neuronal excitation in the DR was weakened after colitis. These phenomena were associated with a loss of normally occurring inhibitory effect of the compound's high doses on hemodynamic reactions to CRD and TS, revealing deficient antinociceptive action at a systemic level. The data suggest postcolitis changes in buspirone-dependent 5-HT1A autoreceptor- and heteroreceptor-mediated signalling, which can directly or indirectly lead to reduced RMg pain-related activity and increased DR nociceptive excitation, impairing their functioning in the visceral and somatic pain control.